Clinical,radiographic, and genetic diagnosis of progressive pseudorheumatoid dysplasia in a patient with severe polyarthropathy

A 14-year-old boy presented with a 10-year history of the "sicca" form of seronegative juvenile idiopathic polyarthritis. Severely limited range of motion, pain, and capsular swelling in both small and large weight-bearing joints left him wheelchair-bound. Erythrocyte sedimentation rate and C-reactive protein were normal. Two-phase bone scan revealed tracer uptake of almost every joint at both early and late time points, indicating pathologic exudation and enhanced bone metabolism consistent with severe arthritis. However, radiographic studies revealed no erosive arthropathy but severe osteopenia, dysplastic bone changes, mega os trigonum, and platyspondylia. A magnetic resonance imaging (MRI) scan of the hips showed no signs of synovitis, pannus, or effusion but cartilage irregularities and subchondral cysts. These findings strongly suggested the diagnosis of progressive pseudorheumatoid dysplasia of childhood, an autosomal-recessive disorder of cartilage homeostasis. The patient carries a novel homozygous two-nucleotide deletion in exon 4 of the WISP3 gene. This genetic disorder is an important differential diagnosis of sicca polyarthritis.     

Clinical and radiological diagnosis of progressive pseudorheumatoid dysplasia in two sisters with severe polyarthropathy

The aim of this case report is to describe unusual cases of progressive pseudorheumatoid dysplasia (PPD) affecting the axial skeleton and peripheral joints and to stress the importance of examining the entire skeleton for definite diagnosis and the importance of rehabilitation interventions. PPD is a rare familial disease characterized by generalized bone–cartilage dysplasia, progressive arthropathy, and platyspondyly. PPD presents as spondyloepiphyseal dysplasia (SED) tarda with progressive arthropathy and progressive pseudorheumatoid arthritis of childhood and is described as a specific autosomal recessive subtype of SED. Two sisters, 18 and 16 years old, with low back pain and polyarthritis are presented. Radiographic and magnetic resonance imaging of the cases revealed typical features characteristic for PPD-like platyspondyly, multiple intravertebral herniations, changes in metaphyses and epiphysis, and mega os trigonum. Consequently, PPD is a rare disease of childhood and should be kept in mind in the differential diagnosis of juvenile idiopathic arthritis to prevent delayed diagnosis and to begin rehabilitation interventions early. It is essential to carefully examine the entire body, particularly the axial skeleton, and to perform radiological evaluation of the spine. These illustrative cases serve to remind physicians to examine the entire skeleton and not to concentrate only on branches but also on the trunk.     

Chitotriosidase activity in juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is an inflammatory joint disease of unknown etiology. The pathogenesis is driven by T and B cells. The role of macrophages remains unclear. Chitotriosidase belongs to the chitinase protein family and is secreted by activated macrophages. The chitinases are able to catalyze the hydrolysis of chitin or chitin-like substrates such as 4-methylumbelliferyl chitotrioside. Chitotriosidase activity was determined using the substrate 4-methylumbelliferyl beta-DNN'N'-triacetylchitotrioside (4-MU-TCT, SIGMA Chemical Co.). The substrate and serum were incubated with the serum in a citrate/phosphate buffer. The reaction was stopped by adding a buffer (Na(2)CO(3)). The fluorescence of 4-methylumbelliferone was evaluated by fluorimeter at excitation 360 nm and emission 450 nm. We report about chitotriosidase measurements in patients with JIA. The chitotriosidase level in synovial fluid was up to approximately 1,000 nmol/(h ml) at disease onset before therapy. The level in the sera was below 600 nmol/(h ml). Serum chitotriosidase levels could represent the activity of macrophages in the synovial fluid in JIA.     

Switching the therapy from etanercept to infliximab in a child with rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Tumor necrosis factor α (TNFα)-blocking agents have been used increasingly in the treatment of severe refractory juvenile idiopathic arthritis (JIA). However, some patients have been forced to discontinue these agents because of the lack of efficacy or adverse events. In these situations, cases of switching from one TNF-blocking agent to another are reported in rheumatoid arthritis, but there are few cases in JIA. This report documents the case of a patient with JIA who improved following a switch from etanercept to infliximab.     

Switching the therapy from etanercept to infliximab in a child with rheumatoid factor positive polyarticular juvenile idiopathic arthritis

Abstract

Tumor necrosis factor α (TNFα)-blocking agents have been used increasingly in the treatment of severe refractory juvenile idiopathic arthritis (JIA). However, some patients have been forced to discontinue these agents because of the lack of efficacy or adverse events. In these situations, cases of switching from one TNF-blocking agent to another are reported in rheumatoid arthritis, but there are few cases in JIA. This report documents the case of a patient with JIA who improved following a switch from etanercept to infliximab.     

Analysis of childhood reactive arthritis and comparison with juvenile idiopathic arthritis

There is currently no agreement on how to classify and diagnose reactive arthritis (ReA) and what kind of clinical and laboratory findings are specific for the diagnosis. This study retrospectively analyzed the initial clinical manifestations and laboratory findings in children diagnosed with ReA and juvenile idiopathic arthritis (JIA). A comparison was also made between these two groups to see if there were differences. A retrospective chart review was performed and 44 patients diagnosed with ReA and 80 patients with JIA were enrolled in this study. Their initial clinical manifestations and laboratory findings were also analyzed and compared. The initial clinical manifestations in ReA were analyzed including the demographic data, the preceding infection history, the duration of the infectious episode to the onset of arthritis, the duration of arthritic symptoms, and the involved joint pattern. Comparison of the initial laboratory findings between patients with ReA and JIA showed significant differences between erythrocyte sedimentation rates (ESR) in the first hour, platelet counts (p<0.05), and ESR in the second hour (p=0.052). Further, comparing ReA with the subtypes of JIA, significant differences were noted between ReA and the systemic type in terms of hemoglobin level, platelet counts, C-reactive protein, and first and second hour ESR (p<0.05). However, if compared with the polyarticular or pauciarticular type, only the platelet counts showed any significant statistical difference (p<0.05). This study summarizes clinical experiences in ReA. The differences in laboratory findings of ReA and JIA may provide a clue in making a differential diagnosis.     

临床放射和基因诊断的进行性假性类风湿发育不良症一例并文献复习

目的 提高对WISP3基因突变明确的进行性假性类风湿发育不良症的认识.方法 回顾性分析1例进行性假性类风湿发育不良症的临床表现、实验室检查、影像学改变及基因突变,并通过文献复习进行分析总结.结果 患者男性,无家族史,发病年龄为10岁,首发症状为足跟痛,数月后出现多关节肿痛,累及大小关节、双手和双腕关节伴有腰背痛;基因检查为WISP3基因2种突变,c.589+2T＞C和c.624dupA;患者血清炎性指标均正常;类风湿因子(RF)和抗环瓜氨酸肽(CCP)抗体均为阴性;人类白细胞抗原(HLA)-B27阴性.X线表现关节间隙狭窄,骨质疏松,无关节破坏;骨干骺端或骨端增大;脊柱侧弯畸形,扁平椎,椎间隙普遍变窄,椎体前部上下缘凹陷,中后部凸出;骨盆片骶髂关节和耻骨联合间隙显著增宽.符合进行性假性类风湿发育不良症,其临床症状酷似幼年类风湿关节炎和幼年强直性脊柱炎,但无滑膜炎及其他炎性改变,X线无侵蚀性破坏.结论 进行性假性类风湿发育不良症在国内尚无基因突变报道,是一种少见的常染色体隐性遗传性疾病.基因、实验室检查及典型的影像学表现有助于诊断.本例患者WISP3基因的c.589+2T＞C和c.624dupA突变为国内外首次报道.     

Serological screening for coeliac disease in patients with juvenile idiopathic arthritis

Background and study aimsJuvenile idiopathic arthritis (JIA) is characterized by autoimmune aetiology. A gene locus 4q27 related to rheumatoid arthritis, psoriatic arthritis, and coeliac disease is associated with susceptibility to JIA. There are reports indicating several patients with JIA had been diagnosed with CD. We aimed to assess the frequency of coeliac disease (CD) in patients with juvenile idiopathic arthritis (JIA).Patients and methodsThis prospective study was carried out from October 2015 to August 2016 and included 96 patients with JIA. All patients were evaluated in terms of clinical and laboratory findings of CD. Levels of total IgA and tissue transglutaminase antibody (tTG) IgA were measured in all patients. Those with increased level of tTG IgA were further tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy were planned for a definite diagnosis of CD in patients with positive EMA.ResultsOf the 96 patients in our study, 34 (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had ERA form, 11 (11.5%) had systemic form, and 10 (10.4%) had psoriatic form. Sixteen of our patients (16.6%) were not using any drugs during the study. Neither EMA IgA antibodies were analysed nor gastro-duodenoscopy was performed because no patients were positive for tTG IgA. There was no difference in terms of tTG levels between the patients using NSAIDs or other drugs.ConclusionWe did not find CD in children with JIA. Long term studies with more JIA patients are needed to provide more precise interpretation.     

Hip involvement in juvenile idiopathic arthritis

We analyzed the clinical, biological, and radiological aspects of hip involvement in juvenile idiopathic arthritis (JIA) in a developing country. The recruited patients fulfilled the International League Against Rheumatism criteria for the diagnosis of the JIA. Clinical, biological, and radiological parameters relating to the JIA were collected. Hip involvement was assessed according to clinical and radiological data related to hip disease. One hundred twenty-one patients were included (68 girls and 53 boys). The mean age of the disease onset was 9 ± 4.2 years (1–16 years).The mean age of the patients at the time of the study was 15 ± 10 years (2–46 years). The duration of the disease was 5 ± 8.5 years (0.5–39 years). Forty cases (33%) of the hip involvement were noted. The mean age was 24 ± 10.03 years (3–46 years); the sex ratio was 1:3. The mean duration of the hip disease was 0.6 ± 3.6 years (3–14 years). Hip arthritis seemed to be more frequent in polyarticular and enthesitis-related arthritis. The severity of the hip involvement was significantly correlated with early disease onset, disease duration, subtypes, and high disability (for all these data p < 0.05). This study suggested that in JIA hip involvement was more frequent in enthesitis-related arthritis and polyarticular subtypes. It was correlated with the severity and the early disease onset of the JIA, which was similar to reported data.     

Differential plasma microRNAs expression in juvenile idiopathic arthritis

Objectives. To identify potential novel biomarkers for juvenile idiopathic arthritis (JIA), we evaluated the correlation between plasma expression levels of specific miRNAs and disease characteristics of JIA.

Methods. Differentially expressed miRNAs in JIA plasma were identified by microarray analysis. Five candidate plasma miRNAs with differential expression were further evaluated by qRT-PCR. The correlation between the expression of candidate plasma miRNAs and clinical parameters of JIA patients was assessed.

Results. The expression of miR-16, miR-146a, and miR-223 was higher, and miR-132 was lower, in the plasma of JIA patients as compared with healthy subjects and juvenile ankylosing spondylitis patients (p < 0.05). Plasma miR-16 concentrations were considerably higher for polyarticular JIA patients than oligoarticular JIA patients and correlated with the juvenile arthritis magnetic resonance imaging scores for the hip and plasma interleukin-6 or IL-6 levels. Additionally, miR-146a levels correlated directly with the Juvenile Arthritis Disease Activity Scores in 27 joints, the swollen joint count, the limited joint count, and the juvenile arthritis magnetic resonance imaging scores for the hip, but correlated inversely with plasma tumor necrosis factor-α or TNF-α levels.

Conclusions. This study demonstrates that the expression of plasma miRNAs correlates with JIA disease and suggests that plasma miR-16 and miR-146a have potential novel value for JIA diagnosis.     

Role of musculoskeletal ultrasonography in the detection of subclinical synovitis in oligo and polyarticular juvenile idiopathic arthritis children

Aim of the work

To study the ability of ultrasound to detect subclinical synovitis in children with oligoarticular and polyarticular juvenile idiopathic arthritis (JIA) and to assess the disease activity according to the clinical, laboratory, and musculoskeletal ultrasonographic (MSUS) evaluation.

Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab

Background

Inhibition of interleukin-6 (IL-6) signaling by tocilizumab is highly effective for treatment of refractory juvenile idiopathic arthritis (JIA). It appears that IL-6 plays an important role in the immune response to the influenza virus, but it is not clear whether treatment with tocilizumab affects the severity of influenza.

Methods

We retrospectively collected clinical and laboratory data from JIA patients (n = 33) treated with tocilizumab. Ten patients who developed influenza (tocilizumab group; 10.1 %, 10/99 patient-years) were analyzed. Eleven JIA patients who experienced influenza during conventional treatments, without tocilizumab (control group), were compared with the tocilizumab group.

Results

Of the 10 patients in the tocilizumab group, 6 patients did not have high fever (>38 °C), and the other 4 febrile patients recovered from fever in 1 day. White blood cell counts and lymphocyte counts were significantly lower at the acute phase of infection compared with data from before influenza infection. The degree of fever and level of C-reactive protein in the tocilizumab group were significantly reduced compared with the control group.

Conclusions

IL-6 inhibition by tocilizumab reduced inflammation associated with infection and resulted in mild symptoms during influenza. Leukopenia might be a useful indicator of viral infection, including influenza, during tocilizumab treatment.     

Nitric oxide levels and the severity of juvenile idiopathic arthritis

In this study, we evaluate the distribution of nitric oxide (NO) in the serum of juvenile idiopathic arthritis (JIA) patients, correlating it with parameters of the severity of the disease. Ninety-seven patients with mean age 11.7 years and disease duration 4.8 years, showing active disease or not, grouped as oligoarticular (n = 34), polyarticular (n = 29) and systemic (n = 34) group, presenting uveitis and positive RF with erosive arthritis or active disease and erosions had significantly high levels of NO than the inactive ones. NO correlated with TNF-α in the oligoarticular subtype (P < 0.03), with pain in the polyarticular subtype with active disease (P < 0.04) and with ESR in the systemic subtype with active disease (P < 0.03). TNF-α concentration was high in all patients with active disease, accompanying NO production. The data confirm the production of NO in JIA patients, indicating a possible positive correlation between the production of NO and severity of the disease.     

Anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

Anticyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile idiopathic arthritis (JRA), particularly in those with polyarticular JIA. We analyzed the presence of anti-CCP antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups. One hundred and fifty-nine serum samples were investigated. Forty-five patients were diagnosed with JIA (15 male and 30 female) aged 1.9–17.3 years (median 12.9, mean 11.0). Thirty-eight samples were taken from patients suffering from other autoimmunopathies and 34 patients with other underlying diseases were taken at different time points in their disease course. Under 42 samples were taken from patients with noninflammatory diseases. Enzyme-linked immunosorbent assay (ELISA) was used for the detection of anti-CCP antibodies. Anti-CCP antibodies were found in 6.9% of all samples and in 4.4% patients with JIA. Disease duration and medication did not differ significantly between anti-CCP positive and negative patients. A review of the literature and our own results shows that anti-CCP antibodies can be detected in the sera of only some patients with JIA. Routine determination of anti-CCP cannot be recommended.     

Anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis

Abstract

Anticyclic citrullinated peptide (anti-CCP) antibodies have been detected in patients with juvenile idiopathic arthritis (JRA), particularly in those with polyarticular JIA. We analyzed the presence of anti-CCP antibodies of the IgG class in sera of patients with defined juvenile idiopathic arthritis (JIA) of various subgroups. One hundred and fifty-nine serum samples were investigated. Forty-five patients were diagnosed with JIA (15 male and 30 female) aged 1.9–17.3 years (median 12.9, mean 11.0). Thirty-eight samples were taken from patients suffering from other autoimmunopathies and 34 patients with other underlying diseases were taken at different time points in their disease course. Under 42 samples were taken from patients with noninflammatory diseases. Enzyme-linked immunosorbent assay (ELISA) was used for the detection of anti-CCP antibodies. Anti-CCP antibodies were found in 6.9% of all samples and in 4.4% patients with JIA. Disease duration and medication did not differ significantly between anti-CCP positive and negative patients. A review of the literature and our own results shows that anti-CCP antibodies can be detected in the sera of only some patients with JIA. Routine determination of anti-CCP cannot be recommended.     

Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis

The objective of this report is to explore the balance between serum and synovial fluid levels of interleukin (IL)-18 in children with juvenile idiopathic arthritis (JIA). Blood samples were obtained from 81 children with JIA and 18 control children. Synovial fluid samples were collected from 16 children with oligoarticular JIA. Concentrations of IL-18 were determined using commercial kit. Patients with systemic JIA had higher serum levels of IL-18 than patients with other forms of JIA or control children, both during the active (median, range: 6,240, 1,600–78,750 pg/ml) and inactive (1,615, 513–3,270 pg/ml) phase of disease [analysis of variance (ANOVA), P < 0.05). Levels of IL-18 in sera of children with oligoarticular JIA (255, 89–4,342 pg/ml) were similar to the respective synovial fluid levels (217, 89–1,245 pg/ml). Serum levels of IL-18 were proportional to the erythrocyte sedimentation rate and levels of C-reactive protein, but inversely proportional to the haemoglobin levels. IL-18 appears to be an important mediator of systemic JIA, while it seems of a lesser relevance in pathogenesis of other JIA forms. Therefore, inhibition of IL-18 might be a base for a successful biological therapy for systemic JIA.     

Articular damage in adults with juvenile idiopathic arthritis

The goal of this study was to assess the long-term articular damage in adults with juvenile idiopathic arthritis (JIA) using the Rheumatoid Arthritis Articular Damage (RAAD) score and to determine any associations between the disease-related parameters and RAAD score. Thirty-eight adults identified with JIA at 18 years of age or older with disease duration of at least 5 years were assessed by means of the RAAD score. Patients were divided into three groups according to disease duration as 5-10 years (group 1), 11-15 years (group 2) and more than 16 years (group 3), and into three groups according to JIA subtypes as seropositive polyarticular (group A), seronegative polyarticular (group B), and oligoarticular (group C). Functional disability, functional status, disease activity and depression were measured by Health Assessment Questionnaire (HAQ), Steinbrocker classification, Disease Activity Score 28 (DAS 28), and Beck Depression Inventory, respectively. We investigated any possible associations between the RAAD score and groups, sex, age at onset of the disease, HAQ, Steinbrocker classification, DAS 28, and Beck Depression Inventory. We observed significant differences in RAAD scores according to groups A, B, C (p < 0.01), but not according to groups 1, 2, 3 or sex (p > 0.05). While the RAAD score correlated well with HAQ (p < 0.001), Steinbrocker classification (p < 0.001) and DAS 28 (p < 0.01), it did not correlate with age at onset of the disease (p > 0.05) or Beck Depression Inventory (p > 0.05). Seropositive polyarticular patients demonstrate the worst articular damage scores. Even though articular damage does not progress over time and JIA frequently has a benign course, care should be given to establishing regular follow-up periods and well-arranged treatments, especially for seropositive polyarticular groups, to maintain satisfactory long-term disease outcome throughout the lives of JIA patients.     

Neprilysin levels in plasma and synovial fluid of juvenile idiopathic arthritis patients

Objective Neprilysin (neutral endopeptidase, 3:4:24:11, CD10) (NEP) is a Zn metallopeptidase linked to controlling inflammation through the degradation of neuropeptides involved in neurogenic inflammation of chronic rheumatic diseases. The aim of our study was to evaluate circulating activity and cellular expression of NEP in the plasma of 58 children with juvenile idiopathic arthritis (JIA) and 52 controls. In 20 subjects requiring local steroid injection, NEP was measured in synovial fluid.Methods Plasma and synovial NEP were evaluated using a fluorimetric technique. Neprilysin, expressed as the antigen CD10, was determined on circulating and synovial fluid cells as mean fluorescence intensity (MFI) and as percentage of positive cells by two-color immunofluorescence.Results Circulating NEP levels were lower in JIA patients than in controls (42.0±16.6 vs 76.5±24 pmol/ml per min, P<0.001), while synovial fluid NEP values were higher than circulating levels (241.4±86.2 vs 40±15.3 pmol/ml per min, P<0.001). In monocytes, the percentage of CD10-positive circulating cells and the MFI in JIA were lower than in controls (11.6±5.2% vs 41.4±13%, P<0.001 and 18.1±7.5 vs 31.2±5.4, P<0.05, respectively). On synovial monocytes, the percentage of CD10-positive cells and the MFI were higher than on circulating monocytes (35.2±14.6% vs 9.1±2.4%, P<0.001 and 66.4±5.4 vs 22.8±14.7, P<0.001, respectively).Conclusions The downregulation of CD10 expression in monocytes and the reduction in NEP activity may be linked to the enzymes role in the control of peptides involved in the inflammation. The increased levels of NEP, MFI, and CD10-positive monocytes in synovial fluid, even though in plasma, might reflect a reactive effort to control synovial proliferation.     

幼年特发性关节炎诊疗规范

幼年特发性关节炎(JIA)临床上常见亚型包括全身型JIA、少关节型/多关节型JIA和幼年脊柱关节炎。本病无特异性诊断指标, 需与感染性疾病和恶性病相鉴别。全身型JIA起病多急骤, 病情进展快, 易合并巨噬细胞活化综合征而危及生命。儿童风湿科医生对JIA的诊断及治疗经验仍不足, 规范化诊疗水平有待进一步提高。中华医学会风湿病学分会组织有关专家, 在借鉴国内外诊疗规范和分类标准的基础上, 制定本规范, 旨在规范JIA各亚型及全身型JIA合并巨噬细胞活化综合征的诊断和治疗方案, 以降低致死率和严重并发症的发生率, 从而改善患儿预后。